O06 Juvenile SLE with encephalopathy at onset

Abstract Case report - Introduction A 9.5-year-old girl presented with high-grade fever and rash affecting face, upper arms, chest and back with no other obvious focus. Investigations revealed pancytopaenia, raised inflammatory markers and negative cultures. CT scan of chest and abdomen revealed extensive lymphadenopathy. A diagnosis of juvenile systemic lupus erythematosus (JSLE) was made from the clinical features, including the classical rash and the laboratory profile, after ruling out oncological problems. The diagnosis was complicated by encephalopathy and macrophage activation syndrome, both of which posed therapeutic challenges, but eventually responded to the initial treatment of lupus. Case report - Case description A previously fit and well 9.5-year-old girl of Asian origin, born of non-consanguineous relationship, presented to local hospital with history of high-grade fever (over 39 degree Celsius) and rashes for three weeks. The rash consisted of raised erythematous papules and patches affecting her cheeks, nose, upper arms, chest and back. Her initial blood tests showed anaemia, lymphopaenia and raised inflammatory markers (CRP 47mg/L). She was commenced on broad spectrum antibiotics, which were changed following growth on urine culture. She developed oral ulceration and continued to be lethargic with poor oral intake. High-grade fever persisted with dropping blood counts and inflammatory markers remaining elevated. Further microbiological and immunological (including autoantibody screen) investigations were negative. A CT scan done at this stage showed extensive axillary, mediastinal and abdominal lymphadenopathy. She was transferred to our centre for bone marrow and lymph node biopsies. Her examination revealed cervical and axillary lymphadenopathy, hepatosplenomegaly and ascites, in addition to rashes and oral ulcers. While awaiting the biopsies, she developed multiple episodes of generalised tonic clonic seizures, requiring intubation and ventilation. MRI and MRA of head did not identify an intracranial cause for the encephalopathy. Her rashes were felt to be consistent with lupus and the autoantibody profile showed strongly positive ANA (with coarse speckling pattern) and double-stranded DNA, in addition to profound hypocomplementeamia. She was also positive for Anti SM, RNP and anti-Ro52 antibodies. Her chest radiograph showed pleural effusion while echocardiogram showed global pericardial effusion. She had no proteinuria. The bone marrow and lymph node biopsies ruled out lymphoproliferative pathology. She also satisfied the EULAR (2016) criteria for macrophage activation syndrome (fever, pancytopaenia, ferritin over 32000 microg/L, elevated liver enzymes, hypertriglyceridaemia and hypofibrinogenaemia). The encephalopathy was thought to be due to macrophage activation syndrome (MAS). Case report - Discussion Although her presentation with fever and pancytopaenia with subsequent discovery of extensive lymphadenopathy raised the possibility of lymphoproliferative pathology, the dermatology opinion was clearly favouring JSLE in view of the classical rash. The mouth ulcers, serositis, haematological and immunological profile all supported the diagnosis. She satisfied the clinical and laboratory criteria for MAS, which was thought to be the cause of her encephalopathy too, as there were no changes to suggest lupus or vasculitis, or any other pathology like vascular events or posterior reversible encephalopathy syndrome (PRES), on neuroimaging. She was started on pulse of intravenous methyl prednisolone, which was continued for a further two days due to MAS, followed by cyclophosphamide at 500mg/m2. The plan is to continue cyclophosphamide to induce remission, in addition to slow weaning course of oral steroids and hydroxychloroquine. She had an excellent clinical and laboratory response at the first review since discharge. Case report - Key learning points 1) The initial diagnosis with fever and extensive lymphadenopathy was challenging, although it has been reported in the literature as more common in childhood-onset lupus, when compared to lupus presenting in adulthood. The multi-disciplinary team working involving the rheumatology, dermatology, neurology and oncology teams made the diagnostic process more efficient and timely. 2) The diagnostic dilemma over the cause of encephalopathy with neuroimaging suggestive of no changes suggestive of lupus, vasculitis, vascular events or other pathology like PRES (although the seizures occurred prior to use of steroids and she had no evidence of hypertension or renal involvement). Although difficult to prove, we put this down to MAS and she had a significant clinical improvement, in line with improvement of laboratory parameters of MAS. 3) Her MAS settled down with steroids, without having to resort to alternate agents like cyclosporine or anti-interleukin1 agents. The choice of agent to treat MAS, had it not settled down with the initial pulse of steroids, was debated – we would have had to choose an agent that may not be as effective in the management of lupus. We were not comfortable with choosing two different agents to treat the condition and a complication of the condition; but the extended course of steroids worked well for both.

became progressively impaired eventually requiring a wheelchair for any outdoor excursion. The systemic and musculoskeletal symptoms were attributed to a paraneoplastic manifestation of his malignant process. A rheumatology opinion was eventually requested in view of the persistence of joint symptoms despite effective cancer treatment with radical radiotherapy. He described early morning stiffness lasting more than 3 hours. Synovitis was evident at his hands, wrists and knees, whilst shoulder movement was restricted, resulting in a high disease activity score (DAS) of 7.44. Blood workup showed normal rheumatoid factor and cyclic citrullinated peptide (CCP). Acute phase markers were elevated with ESR 99 mm/hr, CRP 79 mg/l and ferritin 1194 ng/ml. Ultrasound (US) hands confirmed widespread active synovitis involving bilateral wrist and metacarpophalangeal joints. X-rays showed only degenerative changes. A diagnosis of seronegative inflammatory arthritis was established, and he was initiated on hydroxychloroquine with reducing regime of prednisolone. Methotrexate (MTX) was briefly deferred pending oncology advice. Following initiation of MTX he improved dramatically, returning to normal mobility, and steroids were successfully tapered off. Case report -Discussion: Our patient had symptoms of inflammatory arthritis prior to identification of a SCC with local spread; however, his systemic and musculoskeletal features were initially regarded as paraneoplastic. Paraneoplastic arthritides encompass the musculoskeletal manifestations of malignancy. This includes polyarthritis, inflammatory myopathies, hypertrophic osteoarthropathy and palmar fasciitis. Symptoms may precede or occur concurrently with cancer presentations and often respond to treatment of the underlying cancer. Persistence of musculoskeletal symptoms may be a clue to co-existence of a rheumatic diagnosis. Reassessment of history and examination can guide physicians to a concurrent second diagnosis when clinical progress is not as expected. Our case also highlights the question of safe use of immunosuppressive drugs in rheumatic patients with cancer and whether they may promote or induce malignant disease. Literature is challenging to assess as many systemic inflammatory disorders, including RA, have an established increased risk of certain cancers, including lymphoproliferative disease. He was managed by prednisolone and hydroxychloroquine, followed rapidly by MTX, leading to dramatic symptomatic improvement. Low-dose MTX (25-30mg weekly) is considered first-line treatment in RA. Of the commonly used anti-rheumatic therapies it has the least evidence to suggest a potential increased malignancy risk. Other antirheumatic drugs such as Tumour Necrosis Factor (TNF) inhibitors also have a favourable risk profile regarding cancer development. Most observational studies evaluating the use of biologic therapy in RA patients with previous solid tumours do not show an increased risk of recurrence. Coordination of care with the patient and their oncologist is essential in the management of cases of individuals with rheumatic disease and concomitant cancer. Case report -Key learning points: 1. Cancer is often considered with certain rheumatic presentations but sometimes it is equally important to look for concomitant rheumatic disease when patients with cancer have musculoskeletal symptoms. 2. As cancer can mimic the early systemic features of arthritis and patients will often delay seeking medical advice, clinicians should be alert to the possibility of co-existent disease and ensure careful assessments at clinical encounters. 3. The treatment of rheumatic disease in a patient with cancer may be of equal importance to the individual resulting in reduced quality of life, sometimes with greater impact than that of the cancer itself. 4. Many anti-rheumatic therapies have a favourable profile regarding the risk of de novo malignancy and recurrence. 5. For patients with rheumatic disease and active or previous cancer, clinical decision-making should carefully weigh up the risks and benefits of treatments for both conditions. Therapeutic options should be considered between rheumatologist, oncologist, and patient, taking into account prognosis, quality of life and patient choice.

CHILDHOOD ONSET LUPUS O06 JUVENILE SLE WITH ENCEPHALOPATHY AT ONSET
Kishore Warrier, Vishal Paisal and Samundeeswari Deepak Nottingham University Hospitals, Nottingham, United Kingdom Case report -Introduction: A 9.5-year-old girl presented with highgrade fever and rash affecting face, upper arms, chest and back with no other obvious focus. Investigations revealed pancytopaenia, raised inflammatory markers and negative cultures. CT scan of chest and abdomen revealed extensive lymphadenopathy. A diagnosis of juvenile systemic lupus erythematosus (JSLE) was made from the clinical features, including the classical rash and the laboratory profile, after ruling out oncological problems. The diagnosis was complicated by encephalopathy and macrophage activation syndrome, both of which posed therapeutic challenges, but eventually responded to the initial treatment of lupus.
Case report -Case description: A previously fit and well 9.5-year-old girl of Asian origin, born of non-consanguineous relationship, presented to local hospital with history of high-grade fever (over 39 degree Celsius) and rashes for three weeks. The rash consisted of raised erythematous papules and patches affecting her cheeks, nose, upper arms, chest and back. Her initial blood tests showed anaemia, lymphopaenia and raised inflammatory markers (CRP 47mg/L). She was commenced on broad spectrum antibiotics, which were changed following growth on urine culture. She developed oral ulceration and continued to be lethargic with poor oral intake. High-grade fever persisted with dropping blood counts and inflammatory markers remaining elevated. Further microbiological and immunological (including autoantibody screen) investigations were negative. A CT scan done at this stage showed extensive axillary, mediastinal and abdominal lymphadenopathy. She was transferred to our centre for bone marrow and lymph node biopsies. Her examination revealed cervical and axillary lymphadenopathy, hepatosplenomegaly and ascites, in addition to rashes and oral ulcers. While awaiting the biopsies, she developed multiple episodes of generalised tonic clonic seizures, requiring intubation and ventilation. MRI and MRA of head did not identify an intracranial cause for the encephalopathy. Her rashes were felt to be consistent with lupus and the autoantibody profile showed strongly positive ANA (with coarse speckling pattern) and double-stranded DNA, in addition to profound hypocomplementeamia. She was also positive for Anti SM, RNP and anti-Ro52 antibodies. Her chest radiograph showed pleural effusion while echocardiogram showed global pericardial effusion. She had no proteinuria. The bone marrow and lymph node biopsies ruled out lymphoproliferative pathology. She also satisfied the EULAR (2016) criteria for macrophage activation syndrome (fever, pancytopaenia, ferritin over 32000 microg/L, elevated liver enzymes, hypertriglyceridaemia and hypofibrinogenaemia). The encephalopathy was thought to be due to macrophage activation syndrome (MAS). Case report -Discussion: Although her presentation with fever and pancytopaenia with subsequent discovery of extensive lymphadenopathy raised the possibility of lymphoproliferative pathology, the dermatology opinion was clearly favouring JSLE in view of the classical rash. The mouth ulcers, serositis, haematological and immunological profile all supported the diagnosis. She satisfied the clinical and laboratory criteria for MAS, which was thought to be the cause of her encephalopathy too, as there were no changes to suggest lupus or vasculitis, or any other pathology like vascular events or posterior reversible encephalopathy syndrome (PRES), on neuroimaging. She was started on pulse of intravenous methyl prednisolone, which was continued for a further two days due to MAS, followed by cyclophosphamide at 500mg/m2. The plan is to continue cyclophosphamide to induce remission, in addition to slow weaning course of oral steroids and hydroxychloroquine. She had an excellent clinical and laboratory response at the first review since discharge. Case report -Key learning points: 1) The initial diagnosis with fever and extensive lymphadenopathy was challenging, although it has been reported in the literature as more common in childhood-onset lupus, when compared to lupus presenting in adulthood. The multi-disciplinary team working involving the rheumatology, dermatology, neurology and oncology teams made the diagnostic process more efficient and timely.
2) The diagnostic dilemma over the cause of encephalopathy with neuroimaging suggestive of no changes suggestive of lupus, vasculitis, vascular events or other pathology like PRES (although the seizures occurred prior to use of steroids and she had no evidence of hypertension or renal involvement). Although difficult to prove, we put this down i4 https://academic.oup.com/rheumap to MAS and she had a significant clinical improvement, in line with improvement of laboratory parameters of MAS.
3) Her MAS settled down with steroids, without having to resort to alternate agents like cyclosporine or anti-interleukin1 agents. The choice of agent to treat MAS, had it not settled down with the initial pulse of steroids, was debated -we would have had to choose an agent that may not be as effective in the management of lupus. We were not comfortable with choosing two different agents to treat the condition and a complication of the condition; but the extended course of steroids worked well for both. Case report -Introduction: Juvenile-onset systemic lupus erythematosus (jSLE) is a rare systemic autoimmune-disease affecting children, with an incidence between 0.5 and 6 per 100,000. A 20-year-old female with known jSLE was diagnosed six years ago, age 14, following multiple attendances to A&E with non-specific symptoms. She was initially discharged with simple analgesia but later admitted to the paediatric ward with severe central chest pain. Investigations confirmed pleuro-pericardial effusion and positive lupus antibodies. She subsequently had recurrent flares with predominantly renal involvement. She remained symptomatic despite multiple combined immunosuppressive agents including biological therapies. Unfortunately, her kidney-functions deteriorated, requiring close monitoring in the Advanced Kidney-Care Clinic. Case report -Case description: A 14-year-old female who was otherwise fit and healthy with no family history of autoimmune conditions presented to the Emergency department with constant throbbing limbpain and recurrent episodes of chest pains. Immunological investigations revealed positive anti-nuclear antibodies (ANA), anti-double-stranded(ds)-DNA antibodies, C1Q-antibody and lupus inhibitor on two repeat tests. Echocardiogram showed pleuropericardial effusion and due to the high risk of cardiac tamponade, she was transferred to a tertiary centre for further management. She had intravenous steroid with good resolution of symptoms, and subsequently received maintenance therapy of azathioprine and hydroxychloroquine. She stayed in remission for approximately one year before her clinical condition worsened. She started to develop active inflammatory arthritis and serositis, with increasing anti-dsDNA titres, reducing complement levels, worsening anaemia and a positive direct antiglobulin test. Oral corticosteroids were recommenced and azathioprine was switched to mycophenolate-mofetil. She subsequently had recurrent flares; predominantly renal involvement and worsening proteinuria. This did not improve with repeat courses of antibiotics given for presumed urinary tract infections (UTIs), prompting renal biopsy which confirmed active renal lupus (combined Class III and V lupus nephritis). Rituximab and tacrolimus were initiated but rituximab was withheld after the first dose due to severe, widespread desquamating rash, mucosal ulceration and fever, biopsy-proven and drug-induced. Short-term remission after 1 dose of rituximab and then renal relapse with repeat renal biopsy showed class 5 lupus nephritis. Intravenous cyclophosphamide with Euro-lupus regimen was given. 5 months after discontinuation of cyclophosphamide her renal disease relapsed again with rising anti-dsDNA, ESR and proteinuria to > 6g/l, despite mycophenolate. Repeat and extended course of cyclophosphamide was restarted. Combination MMF and tacrolimus did not maintain control of disease and renal function continued to decline. Belimumab IV-monthly was added in combination and proteinuria halved, with stabilisation of renal function, although now with eGFR 25ml/min. The most recent biopsy shows chronic damage. SLEDAI-improved from 22 to 10. Case report -Discussion: In children, adolescent females are predominantly affected as observed in this case. The peak age of onset is around 12 years, often with more severe disease presentation than lupus in adults; with a higher incidence of major organ involvement and aggressive disease course with a higher chance of developing complications. She developed uncontrolled hypertension and nephrotic syndrome requiring treatment with multiple antihypertensive agents and thrombosis prevention with DOACs. The patient was offered but refused anaemia treatment with erythropoietin. She received infection prevention treatment (PCP prophylaxis) and GnRH agonist injections to preserve ovarian function while on cyclophosphamide. Later, she developed iatrogenic cushingoid syndrome and severe facial acne. Poor compliance, commonly seen in this age group, possibly contributed to the poor outcomes. Other medication-related complications included retinal hydroxychloroquine toxicity that led to dose reduction. Allergy to rituximab (Mabthera) prevented its further use; given the severity of reaction concerns, other biosimilar humanized anti-CD20 antibodies were considered, but difficult to obtain; deteriorating renal function with predominantly damaged kidneys and class V nephritis on biopsy and aiming to control immunology along with other active symptoms (arthritis, serositis-pleurisy, systemic symptoms, anaemia) options were limited. There was increasing evidence to use belimumab plus tacrolimus þ/-Mycophenolate-Mofetil to maintain remission. Belimumab was used after a repeat course of cyclophosphamide for this patient, after discussion with tertiary renal centres. During the course of her illness, she had progressively deteriorating renal function, which prompted discussion for renal replacement therapy or renal transplant. Considering that this was affecting her at such a young age, she was advised to keep an up-to-date vaccination status. Her worsening condition as well as its associated complications related to treatment and polypharmacy have significantly affected her mental health and quality of life in many ways, including suffering from depression and fatigue. Frequent hospital visits for investigations and treatment also hampered her education. This emphasizes the importance of social, family, and educational support for patients with this condition.

ORAL ABSTRACT PRESENTATIONSCHILDHOOD ONSET
In conclusion, despite a multidisciplinary approach and access to specialist services severe relapsing course of SLE and multiple diseases and treatment-related complications developed with co-morbidity, leading to life-changing organ damage and impact on quality of life. Case report -Key learning points: 1. In paediatric presentations, vague symptom onset and presentation to general practice and general paediatrics with a rare condition can lead to delay in initial diagnosis. She presented initially with multiorgan involvement, serositis, and joints involvement later despite having combination immunosuppressive therapies; having recurrent flares leading to persistent proteinuria and end-stage renal failure indicates an aggressive disease course in children. 2. Managing complications related to SLE such as anaemia, hypertension, nephrotic syndrome and depression is challenging and requires multi-disciplinary input. Clinicians need to be aware of side effects/complications of immunosuppressive therapies in children and sometimes withdrawal of offending agents can help in resolution. 3. DVT prophylaxis in high-risk lupus profile and nephrotic syndrome-lupus nephritis with anticoagulation therapy is mandatory and contraception with progesterone-only-products is recommended owing to less risk of DVT. 4. Response and bioavailability of potent immune-modulating drugs differ between adults and children. Side effects of drugs can be particularly problematic in adolescents. They can have a dramatic impact on education, social development, and the whole family. 5. If allergy precludes the use of rituximab, availability of other anti-CD20-monoclonal antibody drugs is still very limited 6. There is increasing evidence that belimumab (monoclonal antibody) can also have a benefit on renal lupus. 7. Patients with lupus nephritis are at risk of chronic kidney disease and it would be appropriate to have up-to-date immunization-status in case the patient needs renal transplant consideration in the future. 8. Patients should be able to continue study and in view of symptoms and the disruption due to illness, the hospital should offer support letters to schools/universities to enable flexibility with assignments and time extension. To conclude, jSLE is a challenging disease that is both difficult to diagnose and to treat. Clinicians should be aware of the greater risk of systemic complications in children with SLE.